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Phase 1 study of safety, pharmacokinetics, and pharmacodynamics of tivantinib in combination with bevacizumab in adult patients with advanced solid tumors

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Abstract

Purpose

We investigated the combination of tivantinib, a c-MET tyrosine kinase inhibitor (TKI), and bevacizumab, an anti-VEGF-A antibody.

Methods

Patients with advanced solid tumors received bevacizumab (10 mg/kg intravenously every 2 weeks) and escalating doses of tivantinib (120–360 mg orally twice daily). In addition to safety and preliminary efficacy, we evaluated pharmacokinetics of tivantinib and its metabolites, as well as pharmacodynamic biomarkers in peripheral blood and skin.

Results

Eleven patients received the combination treatment, which was generally well tolerated. The main dose-limiting toxicity was grade 3 hypertension, which was observed in four patients. Other toxicities included lymphopenia and electrolyte disturbances. No exposure-toxicity relationship was observed for tivantinib or metabolites. No clinical responses were observed. Mean levels of the serum cytokine bFGF increased (p = 0.008) after the bevacizumab-only lead-in and decreased back to baseline (p = 0.047) after addition of tivantinib. Tivantinib reduced levels of both phospho-MET (7/11 patients) and tubulin (4/11 patients) in skin.

Conclusions

The combination of tivantinib and bevacizumab produced toxicities that were largely consistent with the safety profiles of the individual drugs. The study was terminated prior to establishment of the recommended phase II dose (RP2D) due to concerns regarding the mechanism of tivantinib, as well as lack of clinical efficacy seen in this and other studies. Tivantinib reversed the upregulation of bFGF caused by bevacizumab, which has been considered a potential mechanism of resistance to therapies targeting the VEGF pathway. The findings from this study suggest that the mechanism of action of tivantinib in humans may involve inhibition of both c-MET and tubulin expression.

Trial registration

NCT01749384 (First posted 12/13/2012).

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Funding

Grants UM1-CA186690, U24CA247643 (NCI-CTEP), and R50CA211241 (NCI). This project used the UPMC Hillman Cancer Center Pharmacokinetics and Pharmacodynamics Facility (CPPF) and was supported in part by award P30-CA47904. This project used the UPMC Hillman Cancer Center and Tissue and Research Pathology/Pitt Biospecimen Core shared resource which is supported in part by award P30-CA047904. WFM was supported by the Hillman Cancer Center Cancer Training in Cancer Therapeutics Research Grant (T32 CA193205).

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Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    William F. Maguire, John C. Schmitz, Shannon Puhalla, John Rhee, Ronald Stoller, James J. Lee, Jan H. Beumer, Edward Chu & Leonard J. Appleman

  2. Cancer Therapeutics Program, UPMC Hillman Cancer Center, 5150 Centre Avenue, Pittsburgh, PA, USA

    William F. Maguire, John C. Schmitz, Jonas Scemama, Ken Czambel, Yan Lin, Shaoyu Wu, Shannon Puhalla, John Rhee, Ronald Stoller, James J. Lee, Jan H. Beumer, Edward Chu & Leonard J. Appleman

  3. UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    William F. Maguire, Yan Lin, Shannon Puhalla, John Rhee, Ronald Stoller, James J. Lee, Jan H. Beumer, Edward Chu & Leonard J. Appleman

  4. Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA

    Jan H. Beumer

  5. UPMC Hillman Cancer Center Biostatistics Facility, Pittsburgh, PA, USA

    Yan Lin

  6. Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

    Yan Lin & Huang Lin

  7. Pitt Biospecimen Core Research Histology Department, Health Sciences Core Research Facilities, Pittsburgh, PA, USA

    Anthony G. Green

  8. School of Pharmaceutical Science, Southern Medical University, Guangzhou, China

    Shaoyu Wu

  9. Roche Product Development, Roche (China) Holding Ltd., Shanghai, China

    Huang Lin

  10. Department of Melanoma and Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    Hussein Tawbi

  11. Cancer Therapy Evaluation Program, National Cancer Institute, NIH, Bethesda, MD, USA

    John J. Wright

  12. Department of Oncology and Cancer Therapeutics Program, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY, USA

    Edward Chu

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  1. William F. Maguire
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ETCTN-9153 Study Team

Corresponding author

Correspondence to Leonard J. Appleman.

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The authors declare that they have no conflict of interest.

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The study was approved by the Institutional Review Board at the University of Pittsburgh and was conducted in accordance with the Declaration of Helsinki for human subject protection. All patients provided written informed consent prior to enrollment.

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Maguire, W.F., Schmitz, J.C., Scemama, J. et al. Phase 1 study of safety, pharmacokinetics, and pharmacodynamics of tivantinib in combination with bevacizumab in adult patients with advanced solid tumors. Cancer Chemother Pharmacol 88, 643–654 (2021). https://doi.org/10.1007/s00280-021-04317-y

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